Prolactin, which is produced and secreted from anterior lobe of the pituitary gland, shows a variety of actions including the actions on mammary glands to play an important role for starting and maintenance of lactation, the actions on water-electrolyte metabolism, the actions on reproductive glands, the actions on the immune system and the actions on brain function. The prolactin-producing cells of the pituitary gland are recognized to have clearly characteristic properties. For example, peptide hormones so far known as various pituitary hormone secretion/production stimulating hormones secreted from hypothalamus are clearly observed to act preferentially and specifically on specified pituitary hormone secretion/production cells of the anterior lobes of the pituitary gland. Typically, while gonadotropic hormone releasing hormone, sometimes referred to as GnRH (gonadotropin releasing hormone): lutenizing hormone-releasing hormone (LH-RH), acts preferentially and specifically on the cells which secrete/produce, for example, follicle stimulating hormone (FSH) and lutenizing hormone (LH) in the anterior lobe of pituitary, no observational studies have been reported that the GnRH acts on the cells which produce/secrete prolactin, also known as an anterior pituitary hormone, to cause secretion of prolactin. Therefore, cells which produce/secrete gonadotropins and prolactin are considered to have, among anterior pituitary hormone secreting/producing cells, entirely different characteristic features. From the viewpoints as above, for controlling the prolactin production/secretion, the drug to be used therefor should at least act on pituitary prolactin-producing cells which can be clearly distinguished from other peptide hormone secretion/production cells of pituitary.
As diseases caused by excess production and secretion of prolactin, hyperprolactinemia has been known, which shows clinical symptoms such as suppression of reproductive function and galactorrhea (cf. Clinical Neuroscience, Vol.8, No.4, 1990, Chugai Igakusha; Nihon Rinsho, Vol.51, No.10, 1993, Nihon Rinshosha). As causes of this hyperprolactinemia, prolactin-secreting pituitary tumor (prolactinoma) is frequently observed, and, besides, functional hyperprolactinemia due to paracrisis of prolactin-inhibiting factor or drug-induced hyperprolactinemia have been known (cf. Clinical Neuroscience, Vol.8, 1990, Chugai Igakusha; Nihon Rinsho, Vol.51, No.10, 1993, Nihon Rinshosha). Furthermore, prolactin takes part also in puerperal lactation and galactorrhea.
Hyperprolactinemia is treated principally by surgical operation and drug treatment. As the drug for treatment, a dopamine agonistic one such as bromocriptine is used, leaving several problems still to be solved. First of all, bromocriptine therapy is not a complete cure, and, after suspension of the administration, the prolactin levels rise up again and the recurrence and progression of the disease are observed. And, undesirable side effects, including digestive symptoms such as nausea, vomiting and constipation, postural hypotension and headache, are observed. Further, among prolactin adenomas, there exist bromocriptine-resistant ones. For solving these problems, development of a novel agent of suppressing prolactin-production has been desired.
Condensed bicyclic compounds, for example, a thieno[2,3-b]pyridine derivative and a thieno[2,3-d]pyrimidine derivative, are known to have an excellent gonadotropic hormone-releasing hormone antagonistic activity (PCT International Publication No. WO95/28405). On the other hand, while the pituitary prolactin-producing cells have so far been considered to be clearly distinguished from other pituitary peptide hormone secreting/producing cells, especially FSH- or LH-secreting/producing cells, among peptide pituitary hormone secretion/production stimulating hormone actually secreted from hypothalamus, none of such hormone as acting on prolactin-producing cells to cause secretion of prolactin while showing simultaneously activity on gonadotropin secreting/producing cells has been known. Circumstances being such as above, development of a novel agent of suppressing prolactin-production from an independent viewpoint has been required as well.
Furthermore, for treating diseases/disturbances due to hyperprolactin, use of a prolactin inhibitory agent acting specifically on prolactin-producing cells has a possibility of curing completely hyperprolactinemia and of reducing undesirable side-effects. Therefore, a highly stable and orally administrable prolactin-inhibiting agent, which is capable of directly suppressing or inhibiting the prolactin-production of pituitary prolactin-producing/secreting cells, especially a non-peptide prolactin inhibitory agent, is ardently desired.